Low-dose vs. Normal-dose Psychostimulants on Executive Functions in Individuals With ADHD
NCT ID: NCT02167048
Last Updated: 2024-05-08
Study Results
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Basic Information
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ACTIVE_NOT_RECRUITING
PHASE1/PHASE2
52 participants
INTERVENTIONAL
2014-06-30
2024-12-31
Brief Summary
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The investigators hypothesize that the lower-dose psychostimulants will result in better cognitive performance than moderate-to-high doses of psychostimulants.
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Detailed Description
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Symptoms are divided into inattention (e.g., easily distracted, difficulty focusing on \& completing a task), hyperactivity (e.g., constantly in motion, fidgets, squirms, talks non-stop), and impulsivity (e.g., difficult waiting one's turn, interrupting others). Three subtypes of ADHD have been identified: predominantly inattentive (ADHD-I), predominantly hyperactive-impulsive (ADHD-H), and the combined type (ADHD-C).
Psychostimulants in medium to high doses acts to inhibit re-uptake of dopamine by the dopamine transporter (DAT), resulting in increased dopamine concentrations in the synapse. DAT is abundant in the striatum, which is implicated in hyperactivity and impulsivity aspects of ADHD. However, DAT is sparse in prefrontal cortex (PFC), which plays a critical role in subserving executive functions. Executive functions (EFs; also called cognitive control or self-regulation) are a group of processes involved in concentration, focused attention, self-control, cognitive flexibility, problem-solving, and working memory (refs: Diamond, 2013; Jacques \& Marcovitch, 2010). Thus the number of high risk alleles of the gene that codes for the dopamine transporter (DAT1) are associated with hyperactivity (which depends on the striatum) but not inattention or EF deficits (which depend on PFC; refs: Jucaite et al., 2005; Waldman et al., 1998.
The action of low doses of psychostimulants has been shown to be different, however. At low doses psychostimulants has been demonstrated to act preferentially on PFC, increasing dopamine release (refs: Berridge et al., 2006; Schmeichel \& Berridge, 2013; Spencer et al, 2012). Thus, moderate to high doses of psychostimulants (doses most often prescribed for children and youths with ADHD) probably do not improve PFC function or EFs, or worse, may actually impair cognitive function, leaving a patient feeling more in a daze.
Optimal dosing for psychostimulants in children and youths with ADHD is usually determined by parents' reports of improved behaviour, almost never by performance on cognitive measures. We propose to look at cognitive performance on measures of attention, working memory, planning, etc. in children and youths with ADHD on their current dose of psychostimulants and on half that much (order counterbalanced across participants).
Purpose/Objectives: This double-blind crossover study aims to compare cognitive performance (e.g., working memory, selective attention and cognitive flexibility) of children ages 6-18 years diagnosed with ADHD of the combined type (ADHD-C) or inattentive-type (ADHD-IA) and currently on \> 20 mg/day of psychostimulants on their current dose of psychostimulants and on a lower-dose of psychostimulants (half of their current dose), order counterbalanced across subjects.
To give us an estimate of order effects to help us correct for better performance in the 2nd session due simply to taking the same cognitive tests twice (note: the tests are Version A and B), we will also be recruiting healthy volunteers to serve as a control group. This control group will be strictly no intervention.
Hypotheses: The investigators hypothesize that lower-dose psychostimulants will result in better cognitive performance than moderate-to-high doses of psychostimulants.
Conditions
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Study Design
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RANDOMIZED
CROSSOVER
TREATMENT
QUADRUPLE
Study Groups
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Normal-dose Psychostimulant, Low-dose
Normal-dose: Dose participants are currently taking as part of their prescription (on more than or equals to 20 mg/day of Psychostimulants) Low-dose: Half the normal dose
Psychostimulants
Participants will be tested twice 2 weeks apart. All will continue on their normal Psychostimulant dose up until 3 days before the testing day. 3 days before their 1st testing session, half the participants will start on either their current-dose of Psychostimulant or half their current dose depending on the arm they were randomized to (we provide those pills).
To control for different pharmacokinetics of the Psychostimulant medications, a given participant will be tested at roughly the peak time for his/her specific version of Psychostimulant and at the same time of day for his/her two testing sessions.
Low-dose Psychostimulants, Normal-dose
Normal-dose: Dose participants are currently taking as part of their prescription (on more than or equals to 20 mg/day of Psychostimulants) Low-dose: Half the normal dose
Psychostimulants
Participants will be tested twice 2 weeks apart. All will continue on their normal Psychostimulant dose up until 3 days before the testing day. 3 days before their 1st testing session, half the participants will start on either their current-dose of Psychostimulant or half their current dose depending on the arm they were randomized to (we provide those pills).
To control for different pharmacokinetics of the Psychostimulant medications, a given participant will be tested at roughly the peak time for his/her specific version of Psychostimulant and at the same time of day for his/her two testing sessions.
No intervention, No intervention
This arm is completely no intervention, and is ONLY for healthy volunteers. We are testing healthy volunteers of the same age to give us an estimate of order effects to help us correct for better performance in the 2nd session due simply to taking the same tests twice (note: the tests are Version A and B).
No interventions assigned to this group
Interventions
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Psychostimulants
Participants will be tested twice 2 weeks apart. All will continue on their normal Psychostimulant dose up until 3 days before the testing day. 3 days before their 1st testing session, half the participants will start on either their current-dose of Psychostimulant or half their current dose depending on the arm they were randomized to (we provide those pills).
To control for different pharmacokinetics of the Psychostimulant medications, a given participant will be tested at roughly the peak time for his/her specific version of Psychostimulant and at the same time of day for his/her two testing sessions.
Eligibility Criteria
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Inclusion Criteria
* Average to above-average IQ (Parental report of an IQ above 90; we will take their word for it)
* Meet DSM-V criteria for ADHD (Combined type or Inattentive type)
* Currently treated with and responding to oral Psychostimulants \>= 20 mg/day and not on a "drug holiday"
* Stable on current Psychostimulant dose for at least 2 weeks
* Able to communicate (understand, speak, and write) in English without the aid of an interpreter
* Able to execute simple manual response (button-press) as required for our tasks
* The child and parent give assent and consent respectively for the child's participation in this study
Exclusion Criteria
* Have any medical condition that could markedly increase sympathetic nervous system activity (e.g. catecholamine-secreting neural tumor), or who are taking a medication on a daily basis (e.g. pseudoephedrine, oral steroids) that has sympathomimetic activity. Note: regular on-label use of inhalers for asthma (e.g., albuterol, steroidal) is permitted
* Taking any psychotropic medication other than on-label Psychostimulants specifically prescribed to treat ADHD
* Have a major, uncorrected sensory impairment (e.g. significant hearing impairment despite hearing aids)
* Lack sufficient English language skills to perform our tasks
* Are taking medications other than their specifically prescribed Psychostimulants that may affect cognitive skills
* Have a documented history of Dyslexia (this may skew results on our cognitive measures), Bipolar I or II, psychosis, Depression, Autism Spectrum Disorders, or Disruptive Mood Dysregulation Disorder
* Have a past history of any severe adverse reaction to lowering of Psychostiumlant dose
* Patient has been non-compliant with Psychostimulants or is on a "drug holiday"
* Parental report of an IQ below 90 (we will take their word for it)
6 Years
18 Years
ALL
Yes
Sponsors
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University of British Columbia
OTHER
Responsible Party
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Adele Diamond
Principal Investigator
Principal Investigators
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Adele Diamond, Ph.D.
Role: PRINCIPAL_INVESTIGATOR
Department of Psychiatry, University of British Columbia
Locations
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Developmental Cognitive Neuroscience Lab, Department of Psychiatry, University of British Columbia
Vancouver, British Columbia, Canada
Countries
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References
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Barkley RA. Behavioral inhibition, sustained attention, and executive functions: constructing a unifying theory of ADHD. Psychol Bull. 1997 Jan;121(1):65-94. doi: 10.1037/0033-2909.121.1.65.
Diamond A. Executive functions. Annu Rev Psychol. 2013;64:135-68. doi: 10.1146/annurev-psych-113011-143750. Epub 2012 Sep 27.
Jacques, S., & Marcovitch, S. (2010). Development of executive function across the life span. In W. F. Overton (Ed.), Cognition, biology and methods across the lifespan: Volume 1 of the handbook of life-span development (pp. 431-466). Hoboken, NJ: Wiley.
Jucaite A, Fernell E, Halldin C, Forssberg H, Farde L. Reduced midbrain dopamine transporter binding in male adolescents with attention-deficit/hyperactivity disorder: association between striatal dopamine markers and motor hyperactivity. Biol Psychiatry. 2005 Feb 1;57(3):229-38. doi: 10.1016/j.biopsych.2004.11.009.
Waldman ID, Rowe DC, Abramowitz A, Kozel ST, Mohr JH, Sherman SL, Cleveland HH, Sanders ML, Gard JM, Stever C. Association and linkage of the dopamine transporter gene and attention-deficit hyperactivity disorder in children: heterogeneity owing to diagnostic subtype and severity. Am J Hum Genet. 1998 Dec;63(6):1767-76. doi: 10.1086/302132.
Berridge CW, Devilbiss DM, Andrzejewski ME, Arnsten AF, Kelley AE, Schmeichel B, Hamilton C, Spencer RC. Methylphenidate preferentially increases catecholamine neurotransmission within the prefrontal cortex at low doses that enhance cognitive function. Biol Psychiatry. 2006 Nov 15;60(10):1111-20. doi: 10.1016/j.biopsych.2006.04.022. Epub 2006 Jun 23.
Schmeichel BE, Berridge CW. Neurocircuitry underlying the preferential sensitivity of prefrontal catecholamines to low-dose psychostimulants. Neuropsychopharmacology. 2013 May;38(6):1078-84. doi: 10.1038/npp.2013.6. Epub 2013 Feb 6.
Spencer RC, Klein RM, Berridge CW. Psychostimulants act within the prefrontal cortex to improve cognitive function. Biol Psychiatry. 2012 Aug 1;72(3):221-7. doi: 10.1016/j.biopsych.2011.12.002. Epub 2011 Dec 29.
Other Identifiers
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H14-00224
Identifier Type: -
Identifier Source: org_study_id
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